1. Field of the Invention
This invention relates to non-thrombogenic material, and particularly relates to polymeric material heparinized through covalent bonds. Said invention is particularly concerned with a novel procedure for producing said non-thrombogenic material.
2. Description of the Prior Art
In general, contact of blood with nearly any foreign surface leads to blood coagulation. This problem would severely limit the use of many otherwise useful medical procedures. The coagulation is initiated through an activation factor (also known as Hoegeman factor or Factor XII) that activates clotting factors culminating in polymerization of fibrinogen to fibrin. This surface-induced coagulation has presented obvious difficulties in such theraputic procedures as the use of an artifical kidney, heart, lung etc. Without systemic anticoagulants such as heparin, their use would have been impossible. Similarly, heart valves made from metals and polymeric materials produce emboli so that it is necessary to maintain patients on anti-coagulant therapy indefinitely.
In other procedures, for example, catheterization and blood shunting, a choice has had to be made between the systemic heparinization and the risk of clot formation. Systemic anti-coagulation is, of course, not a satisfactory answer due to control problems and the possibility of hemorrhage. In spite of all the foregoing difficulties, it is well known that artificial kidneys and blood oxygenators have been widely used. This is only made possible by administration of heparin, naturally occurring anticoagulant, into the patient's blood stream. Such procedures to prevent clotting are of a short-term nature, since the heparin is ultimately dissipated by the body. Thus, it has long been desirable that a material possessing long-term non-thrombogenic effect be materialized.
The first significant advance toward permanently non-thrombogenic surface has come with the development of heparinized surface by Gott et al. (Gott, V. L., Whiffen, J. D. and Dutton, R., Science 142, 1297 (1963)). In their procedure, graphite is first coated on the polymer surface. The graphite, in turn, serves to absorb a cation, usually benzalkonium group, which then ionically binds heparin molecule. The method of binding heparin to the surface of a polymeric material through a quaternized amine has been further developed by other researchers. In one instance, phenyl groups of polystyrene are chloro-methylated, quarternized with dimethylaniline and then subjected to binding with the heparin. In the above reaction, the heparin is bonded only ionically as a quarternary ammonium salt. The ionically bonded heparin does, in fact, slowly dissociate from the surface in the presence of blood. This means that anti-coagulant properties obtained with ionically-bonded heparin are of a short-term nature.
There have been several attempts with limited success to link or bind heparin covalently to a certain polymer. For example, polyvinyl alcohol is allowed to react with the heparin in the presence of a dialdehyde such as glutaraldehyde. This utilizes the reaction between the aldehydes and the hydroxyls on the adjacent carbon atoms to form 6-membered 1,3-dioxane ring. The procedure can link the heparin to the polymer with a covalent bond, from which permanent non-thrombogenic properties may be expected. The vital drawback of the above procedure lies in the fact that the bi-functional dialdehyde does not always react only between the heparin and the polyvinyl alcohol, but, more likely, reacts between the heparin molecules and also reacts between the polyvinyl alcohol molecules to form many heparin-heparin and polyvinyl alcohol-polyvinyl alcohol cross-linkages. This reaction procedure develops cross-linked heparin gels or the cross-linked polyvinyl alcohols. These products are, of course, unfavorable (undesired) by-products. The ideal picture of the reaction is that one aldehyde in the dialdehyde molecule reacts with the heparin while another aldehyde reacts with the polyvinyl alcohol so that the heparin and the polyvinyl alcohol are bonded each other through aldehyde-OH reaction. Also, as has been known, the anti-coagulant effect of the heparin is remarkably reduced by chemical modifications. Therefore, the linking of the heparin and the polyvinyl alcohol by the action of the dialdehyde can not be called "successful" in view of the fact that the non-thrombogenic property obtained is less than one would expect.